NTA and Fe(III)NTA: differential patterns of renal toxicity in subchronic studies

Abstract

<jats:p> Differential patterns in terms of nephropathology and 8-hydroxyguanine formation in the course of oral 28-day studies were observed with nitrilotriacetic acid (NTA) and FeNTA. FeNTA, but not NTA, caused enhanced 8-hydroxyguanine formation in kidney DNA after oral and intraperitoneal administration. Enhanced lipid peroxidation in the kidney homogenate was observed with FeNTA as well as with NTA. For NTA, the low dose (9 mg/kg per day) was without adverse effect. The kidney toxicity of oral FeNTA (50, 200, and 1000 mg/ kg per day) was only mild, 50 mg/ kg per day; however, it still led to an increased 8-hydroxyguanine content. The relevance of Iron(III) (Fe(III)) or Fe(III)NTA formation as a relevant mediator of NTA-related toxicity was excluded on the basis of these data. Also, a thermodynamic consideration presented here, supports the view that zinc (Zn), and not Fe, is likely to mediate the tubular cell cytotoxicity of NTA. </jats:p>

Effect of melatonin, curcumin, quercetin, and resveratrol on acute ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative damage in rats

“…Also, the level of copper and zinc, elements playing a significant role in antioxidant status of the organism, were measured in the kidney tissue, taking into account the above mentioned interactions, and also the fact that not only Na(3)NTA but also Fe-NTA was reported to exert a high affinity to zinc. 48,49 In our experiment, Fe-NTA administration, both alone or in combination with antioxidants, did not influence renal copper and zinc level.…”

A Rationally Designed Complex Replenishes the Transferrin Iron Pool Directly and with High Specificity

“…31−35 The NTA ligand has also been shown to contribute to toxicity through redistribution of endogenously present Zn. 31 We reasoned that a structurally related tripodal tetradentate ligand functionalized instead with pendant arms to provide an increasingly hard anionic-O coordination sphere, such as 2hydroxybenzyl, would maintain the rapid Fe 3+ transchelation kinetics of NTA while simultaneously increasing Fe 3+ binding affinity and stabilizing the Fe 3+ oxidation state. The effect is illustrated by comparing the pH 7.4 stability constants (log K ML pH 7.4 ) and Fe 3+/2+ redox potentials for the Fe 3+ complexes of the structurally related ligands EDTA and EHPG (Chart 1C,D and Table 1).…”

“…Prior literature evaluating Fe 3+ transchelation reactions demonstrates rapid Fe transfer from nitrilotriacetic acid (NTA, Chart B) to apotransferrin. , Fe-NTA is highly toxic, however, which has been attributed to the release of labile and redox-active Fe. − The NTA ligand has also been shown to contribute to toxicity through redistribution of endogenously present Zn . We reasoned that a structurally related tripodal tetradentate ligand functionalized instead with pendant arms to provide an increasingly hard anionic-O coordination sphere, such as 2-hydroxybenzyl, would maintain the rapid Fe 3+ transchelation kinetics of NTA while simultaneously increasing Fe 3+ binding affinity and stabilizing the Fe 3+ oxidation state.…”

Nitrilotriessigsäure und ihre Natriumsalze [MAK Value Documentation in German language, 2008]

“…ca. 11,2 mg NTA/kg KG) (Leibold et al 2002;Nixon et al 1972). Möglicherweise ist Zink im Urin ein Indikator für auftretende Nierenschäden, die Eingrenzung des entsprechenden Dosisbereichs ist jedoch schwierig, da die Messergebnisse in Nixon et al (1972) schwanken und die Umrechnung der Konzentration von NTA im Futter auf aufgenommene Dosen u. a. vom Rattenstamm abhängt (Anderson 1980) und in der Studie von Anderson (1981) NTA nur 10 Tage lang gegeben wurde.…”

“…Die i.p. Gabe ermöglicht dies, bevor der Fe(III)-NTA-Komplex zum thermodynamisch begünstigten Fe(OH) 3 hydrolysiert (Leibold et al 2002). Es kommt zu Fenton-Reaktionen, dann intrazellulär zu einer ununterbrochenen Bildung von OH-Radikalen, dadurch auch zu einer Anreicherung von 8-Hydroxy-2-desoxyguanosin in der Nieren-DNA von Ratten bei einmaliger i.p.…”